Published on Web 03/20/2002
Asymmetric Diels-Alder Reactions Catalyzed by a Triflic Acid Activated
Chiral Oxazaborolidine
E. J. Corey,* Takanori Shibata, and Thomas W. Lee
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received February 7, 2002
Scheme 1
Chiral oxazaborolidines 1 are very useful catalysts (e.g. with R
) H, Me, n-Bu, or Ar) for the enantioselective reduction of ketones
with BH3‚THF or catecholborane as stoichiometric reductants, a
reaction that is of interest because of its wide scope and the
extraordinary predictive power of the underlying mechanistic
pathway.1,2 We describe herein a new type of catalytic enantiose-
lective Diels-Alder reaction that was inspired by this process and
which employs a proline-derived oxazaborolidine of type 1 as
precatalyst and triflic acid as activator to generate a potent cationic
Lewis acid. In essence, a very strong protic acid is used to create
a very strong Lewis acid, the reverse of the formation of a proton
-
superacid from a Lewis acid, for example HF + BF3 f H+ BF4
.
The reaction of the oxazaborolidine 1, R ) Me and Ar ) C6H5,
with anhydrous triflic acid (ratio 1:1) in CH2Cl2 (or CD2Cl2) results
in the formation of an equilibrium mixture of two N-protonated
species (2 and 3 in Scheme 1) as indicated by low-temperature
(-80 °C) 1H NMR analysis.3 No appreciable amount of triflic acid
appears to be present with these 1:1 mixtures of 1 and triflic acid.
The ratio of 2 to 3 in CD2Cl2 at -80 °C is approximately 1.5:1.
The interconversion of 2 and 3 is slow on the 1H NMR time scale,
but becomes rapid at 0 °C, the coalescence temperature, TC. The
protonation of oxazaborolidine 1 by triflic acid is supported by
downfield shifting (up to 0.5 ppm) of peaks corresponding to the
methylene and methine hydrogens adjacent to nitrogen, and the
appearance of +N-H signals between 6.3 and 6.8 ppm. The species
2 and 3 are stable in CH2Cl2 in the temperature range 0 to -80 °C.
Addition of 1 equiv of DMF results in a 3‚DMF complex, suggested
by the upfield shifting of the B-Me peak from 0.4 to 0.0 ppm.
The Lewis acidity of the cationic Lewis acid 3 was expected to
be high because of its cationic character4,5 and because its formation
requires the very strong triflic acid (methanesulfonic acid generates
relatively weak catalytic activity from 1). These findings place 3
and triflic acid near one another on an effective acidity scale. In
fact, our results on catalysis of Diels-Alder reactions show that
triflic acid and 3 lead to similar reaction rates at -94 °C.
The rationale for the application of 3 to the enantioselective
catalysis of Diels-Alder reactions of R,â-unsaturated aldehydes
is derived from previous research on Lewis superacids and catalytic
enantioselective reaction pathways.4-6 Coordination of the R,â-enal
to 3 was expected to lead to an organized formyl C-H‚‚‚O
hydrogen bonded complex (4 in Scheme 1).4,5 In that complex the
electron-deficient R,â-enal subunit can attract the cis Ar group on
C(5) of the oxazaborolidine ring by a π-π donor-acceptor
interaction (see below).4,5b,6 This attractive interaction will persist
in the Diels-Alder transition state since the formyl carbon maintains
its strong positive charge all along the reaction pathway.4-6
Optimization studies on the application of the cationic ox-
azaborolidine 3 as a catalyst for enantioselective Diels-Alder
reaction to determine the most favorable reaction parameters were
carried out with the results that are summarized in Table 1. As
indicated earlier, triflic acid was more effective than the weaker
methanesulfonic acid (entry 13) in generating an active Diels-
Alder catalyst; the unprotonated oxazaborolidine 1 showed no
catalytic activity (entry 14). The nature of the boron substituent
was found to be important to enantioselectivity, since much lower
enantioselection resulted from the use of 1, R ) Me or Bu, than
from 1, R ) C6H5 (entries 1-3). The best B-aryl substituent found
thus far is o-tolyl (entries 6 and 12-16). Ar ) 3,5-dimethylphenyl
as an aryl substituent in 1 gave better enantioselectivity relative to
Ar ) phenyl in some cases, which is consistent with results from
previous studies and with the neighboring π-donor effect described
above.4,5b,6,7 Independent experiments varying the ratio of 1 to triflic
acid pointed to 1.2:1 as the optimum.
After determination of the most favorable parameters for Diels-
Alder reactions catalyzed by the cationic Lewis acids 3, the scope
of this process for 6A and 6B was studied with the results shown
in Table 2. Excellent yields and enantioselectivities were obtained
with 2-methyl or 2-bromoacrolein and a variety of 1,3-dienes. The
Diels-Alder reactions with reactive dienes such as cyclopentadiene
are fast even at -95 °C, an indication of the very strong Lewis
acidity of the N-protonated catalysts 6A or 6B (rates are somewhat
faster with the former). Good yields and enantioselectivities were
observed for the reactions of the relatively unreactive butadiene
and 1,3-cyclohexadiene, confirming the potent Lewis acidity of 6A
and 6B and suggesting the possibility that a wide range of dienes
can be used in enantioselective Diels-Alder reactions with R,â-
enals.
The absolute configurations of the Diels-Alder products shown
in Table 2 have been assigned by measurement of optical rotation
and comparison with known substances.3,4 Catalysts 6A and 6B
are the only ones known to effect highly enantioselective reaction
between butadiene and 2-methylacrolein.8,9
The absolute stereochemical course of the Diels-Alder reactions
represented in Table 2 can be understood in terms of the type of
catalyst-aldehyde complex shown in 4 and the pre-transition-state
9
3808
J. AM. CHEM. SOC. 2002, 124, 3808-3809
10.1021/ja025848x CCC: $22.00 © 2002 American Chemical Society